Decahydrobenzopyridine quaternaries



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3 022 308 DECAHYDROBENZOI WRIDINE QUATERNARIES Chester John Cavallito and Allan Poe Gray, Decatur,

111., assignors to Irwin, Neisler and Co., Decatur, Ill,

a corporation of Illinois Filed Dec. 3, 1957, Ser. No. 700,280 7 Claims. (Cl. 260286) This invention relates to unsymmetrical bis-(quaternary ammonium)-subs tituted alkane salts, and is more particularly concerned with such compounds wherein the two quaternary ammonium nitrogens are separated by 2 to 4 carbon atoms, inclusive, of the alkane portion of the molecule, wherein the smaller quaternary ammonium group contains up to six carbon atoms and up to one-N- heteromonocyclic group, and wherein the larger quaternary ammonium group is a N-lower-alkyldecahydrobenzopyridinium radical. It is the concept of a composition of matter having a molecular structure wherein this particular larger quaternary ammonium group is separated by 2-4 carbons from the smaller quaternary ammonium group that is the specific inventive feature.

3,022,308 Patented Feb. 20, 1962 i ly ic hygroscopic than those containing the decahydroisoquinolinium group.

The compounds of the present invention have been evaluated by standard pharmacological testing procedures and demonstrated to produce hypotensive activity in living animals. This hypotensive activity is not related to the peripheral ganglionic blocking activity of the compounds and, as a result, this provides the advantage of eliminating many of the undesirable side reactions associated with mal organism orally, intravenously, intramuscularly, sub- The, N lower-alkyldecahydrobenzopyridinium radical includes N lower-alkyldecahydroquinolinium and N- lower-alkyldecahydroisoquinolinium structures wherein the lower-alkyl substituent contains up to about four carbons. j

The smaller quaternary ammonium radical includes trimethylammonium, N-methylpiperidinium, N-methylmorpholinium, N methylpyrrolidinium, dimethylethylampremium and diethylmethylammonium with trimethylammonium and N-methylpyrrolidinium as preferred structures.

The two quaternary ammonium nitrogens may be' separated by 2-4 carbon atoms of the alkane, with separa tion by 2 or 3 carbons being preferred. The alkane chain can be branched chain or straight chain and can contain up to about six carbon atoms.

The quaternary ammonium nitrogens may be attached at the ends of the alkane chain or in any portion therein so long as they nary ammonium group contains up to 6 carbon atoms,

inclusive, and up to one N-teteromonocyclic group; wherein the other quaternary ammonium group is a N-loweralkyldecahydrobenzopyridine radical and, wherein the anions are non-toxic acid residues.

The compounds of the present invention are generally solids, which can exist in the cis or trans form or as mixtures thereof and any and all forms of the compound are intended when not otherwise specified. The isomerism is in the juncture of the two rings of the decahydrobenzopyridine system. Those compounds which contain "the decahydroquinolinium structure are generall-ymore dioxane-alcohol mixtures, et cetera.

J hydrobenzopyridine nucleus.

olines (for example) react more rapidly than do the corcutaneously, and intracutaneously in solid form as in a tablet or in liquid form in water or with any ofthe usual excipients. I i

The compounds of the present invention can be made by the reaction of a suitable haloalkyl quaternary ammonium halide (that which corresponds to all of the desired end molecule save the larger quaternary ammonium moiety) with the appropriate N-lower-alklydecahydrobenzopyridine- The reaction is carried out ina suitable solvent'such as acetonitrile, dimethylformamide, alcohol,

Reaction 'is preferably carried out at reflux temperatures over prolonged time periods /24 days). Some of the starting omegahaloalkyl quaternary ammonium halides are reported in J.A.( 3.S. -77, 3648 (1955) and a type process whereby such class of intermediates can be prepared, for their preparation is described in our copending application Serial 406,053 filed January 25, 1954; which issued December 24, 1957 asU.S. Patent 2,817,664.

The use of a cis or a trans-decahydrobenzopyridine starting base will yield a bis-quaternary ammonium salt product with, respectively, a cisor a trans-fused deca- N-alkyl-cis-decahydroquinresponding trans-isomers, but if the quaternization of a cis-trans mixture of isomeric decahydroquinolines is carried essentially to completion the product will likewise be a mixture of isomers. If, however, two equivalents of a cis-trans mixture of the secondary decahydroquinoline bases are alkylated with one equivalent of an alkyl halide, there is' obtained one equivalent each of transdecahydroquinoline hydrohalide and of an N-alkyl-cisdecahydroquinoline. The latter will then yield a bisquaternary ammonium salt product with a cis-fused decahydroquinoline nucleus. V I

Another method of preparingthe compounds of the present invention which sometimes may be used is to bisquaternize the free diamine base corresponding to the desired end molecule.

The following examples will more particularly illustrate the compounds of the present invention and the procedures whereby they may be prepared, but are not to be construed aslimiting.

. I Example 1 An acetonitrile solution of 5.4 grams (0.035 mole) of .1-methyldecahydroquinoline (cis-trans mixture) and 9.1 grams (0.035 mole) of 3-bromopropyltrimethylammonium bromide was refluxed on the steamhath for 15 hours. The cooled solution was diluted with ether to yield 12.8 grams (88 percent of theory) of trimethylene-l-(l-methyldecahydroquinolinium)-3 (trimethylammonium) dibromide as a hygroscopic solid, melting with gas evolution at 108-110 degrees ccntigrade.

Analysis.-Calculated: C, 46.38; H, 8.29; Br, 38.58. Found: C, 46.11; H, 8.10; Br, 38.15.

Example 2 A-s'olution of 8:0gr'ams (0.05 mole) of Lmethyl-transdecahydroquinoline and 13.6 grams (0.05 mole) of 3- brornopropyltrimethyl-ammonium bromide in isopropyl alcohol was refluxed on the steam-bath for 24 hours. Addition of ether to the cooled solution precipitated an oil which was'diss'olved in ethanol and reprecipitated with ether. Drying the oil over P in vacuo afforded 11.0 grams (51 percent of the theoretical yield) of trimethylene-1-( l-methyl-tran's decahydr'oquinolinium)-3 (trimethylarnmonium) dibrornide as an extremely hygroscopic solid, melting from 130 to 136 degrees centigrade.

Analysis- Calculated: C, 46.38; H, 8.29; Br, 38.58.

Found: c, 45.56; H, 3.27; Br, 38.33.

Example 3 Following the procedure of Example 2, l-ethyldecahydroquinoline (from -a mixture of cis and trans-decahydroquinoline) was reacted with 3-bromopropyltrimethylammonium bromide to yield 65 percent of the theoretical of trimethy lene-1-( 1-ethyldecahydroquinolinium) -3-(trimethylammonium) dibromide, an extremely hygroscopic material. It is'probable that the product is almost en Analysis.-Calculated: Br, 37.32. Found: Br, 37.23. tirely derived from cis-decahydroquinoline.

Example 4 Essentially as described in Example 1, reaction of 1- methyl-trans-decahydroquinoline with 3-bromopropyl-N- methylpyrrolidinium bromide afiorded 52 percent of the theoretical yield of trimethylene- 1-( l-methyl-tr'ans-decahydroquinoliniu'm) -3-( l methylpyrrolidinium) dibromide as a hygroscopic solid melting at 87-88 degrees centi- "grade.

Afialysis.- Calculated: c, 49.09; H, 3.24; Br, 36.30. Found: 0, 43.50; a, 8.08; Br, 3572.

Example 5 A. To 30 grams (0.22'mole) of decahydroquinoline (c-is-trans mixture) was added, dropwise with stirring, a solution of 11."6 grams (0.11 mole) of dimethylaminoethyl chloride in 75 milliliters of benzene. The reaction mixture was refluxed on the steam-bath for 80 hours. Filtering off the precipitate of decahydroquinoline hydrochloride and distilling the residue yielded 9.0 grams (40 percent of theory) of 1-(dimethylaminoethyl)-decahyd'roquinoline, boiling'point 104106 degrees centigrade at 1.5 millimeters, r1 1.4862. Since the decahydroquinolinehyd'rochloride obtained wasshown to be almost pure trans '(melting'point of the base), it is probable that "the product "is essentially derived from cis-decahydroquin anol-ethyl acetate, yielding 9 grams ('72 percent of theory) of ethylene 1 (1-methyldecahydroquinolinium)-2-(trimethylammonium) dibromide as a hygroscopic solid, melting at 142 degrees centigrade With decomposition.

Analysis-Calculated: C, 45.00; H, 8.06; Br, 39.93. Found: C, 44.75; H, 7.78; Br, 39.91.

Example 6 Example 7 Following the general procedure described in Example 6, Z-methyldecahydroisoquinoline was reacted with 3- bromopropyl-l-methylpyrrolidinium bromide to afiord colorless crystals of trimethylene-l-(Z-methyldecahydroisoquinolinium) 3 (l-methylpyrrolidinium) dibromide,

melting point 218-220 degrees centigrade, after several recrystallizations from isopropyl alcohol. 7

Analysis----Calculated: C, 49.09; H, 8.24; Br, 36.30. Found: C, 49.45; H, 8.64; Br, 36.22.

From the isopropyl alcohol mother liquors there was obtained a smaller amount of crystalline material, which melted at 196-499 degrees centigrade after recrystallization from isopropyl alcohol and was apparently "a stereoisomeric trimethylene-1-(2-methyldec ahydroisoquinolinium) -3-( l-methylpyrrolidinium) dibromide.

Analysis.Calculated: C, 49.09; H, 8.24; Br, 36.30. Found: C, 49.32; H, 8.2.9; Br, 36.48.

Example 8 Following the procedure of Example 1, l-butyldecahydroquinoline (cis-trans mixture) was reacted with 4- chlorobutyltrimethyl-ammonium chloride to produce tet- "ramethylehe-l-(1-burtyldeoahydroquinolinium) 4 (trimethylamrnonium) dichloride as a hygroscopic solid.

Example 9 Following the procedure of Example 2, l-ethyl-transdecahydroquinoline was reacted with 3-iodopropyldiethylmethylamrnonium iodide to produce trimethylene-l-(lethyl-trams-decahydroquinolinium) 3-(diethylmethylammoniurn) diiodide as an extremely hygroscopic solid.

Example 10 Example 1 1 Following the'procedure of Example 7, Z-methyldecahydroisoquinoline was reacted with '4-chlo'rohutyltri- 'methylammonium chloride to produce tetramethylene-l- (2-methyldecahydroisoquinolinium) 4 (trimethylammoniu m) dichloride.

"Example 12 Following the procedure of Example 3, 2-ethyldecahydroisoquinoline was reacted with 3-bromopropyltrimethylammonium bromide to produce trimethylene-1-(2-ethyldecahydroisoquinolinium)-3 (trirnethylarnmonium) dih'romide.

. Example 13 7 Following the procedure of Example 7, 2-ethyldecahy- E a droisoquinoline was reacted with 2-br'omoethylriiethylpyrrolidinium bromide to produce ethylene-1-2(-ethyldecahydroisoquinolinium 2 (methylpyrrolidinium) dibromide.

Example 14 Following the procedure of Example 7, 2-butyldecahydroisoquinoline was reacted with B-bromopropyl-N-methylmorpholinium bromide to produce trimethylene-l- (2 butyldecahydroisoquinolinium) 3 (methylmorphm linium) dibromide.

Example 15 Essentially as described in our paper J. Am. Chem. Soc., 77, 3648 (1955), trimethylamine was reacted with l-bromo-2-bromornethylbutane to provide Z-bromomethylbutyltrimethylammonium bromide. Then, following the procedure of Example 1, this was reacted with 1methyldecahydroquinoline (cis-trans mixture) to yield Z-ethyltrimethylene-1 (1 methyldecahydroquinolinium) 3 (trimethyl-ammonium) dibromide.

Example 16 In a similar manner to Example 15, N-methylpyrrolidine was reacted with 2,4-dibromopentane to provide 1-(4-bromo-2 pentyl) l methylpyrrolidinium bromide. Then, following the procedure of Example 7, this was reacted with 2-methyldecahydroisoquinoline to yield 1,3-dimethyltrimethylene-l (Z-methyldecahydroisoquin linium)-3-(l-methylpyrrolidinium) dibromide.

Example 17 In a similar manner to Example 15, trimethylamine was reacted with 1,4-dibromo-2-methylpehtane to provide 4-bromo-2-methyl-l-pentyltrimethylammonium 'bromide. Then, following the procedure of Example 6, this was reacted with Z-methyldecahydroisoquinoline to yield 1,3- -dimethyltetramethylene 1 (Z-methyldecahydroisoquinm linium)-4-(trimethylammonium) dibromide.

Example 18 Two equivalents of decahydroquinoliue (cis-trans mixture) was reacted with 1 equivalent of 1,3-dichloro butane in benzene solution, in a manner similar to that described in Example A, to provide 1-(3-chlorobutyl)- cis-decahydroquinoline. This, reacted with pyrrolidine in essentially the same manner, yielded l-(3-pyrrolidino butyl)-cis-decahydroquinoline, which was then treated with excess methyl iodide to yield l-methyltrimethylene- 3 l methyl-cis-decahydroquinolinium) 1 (l-methylpyrrolidinium) diiodide.

Example 19 I. Acute toxicity (LD by intravenous injection in mice-dosage in terms of milligrams per kilogram of body weight:

Compound of Example: I.V. toxicity 1 67.5

4 63.0 5 31.5 7 (high melting) 60.5

7 (low melting) 62.0

II. Hypo'tensive activity: Effects on the blood pressure of anesthetized dogs:

Compound of Example LV. dose, Percent Duration mgjkg. 13.1. fall hours 0.025 20 0.6 0.05 35 2 0.1 3 7 (high-melting material) 0.01 0. 025 5 0.05 45 2 0.1 65-70 3 7 (low melting material) 0. 5 40 3 0.1 55-60 3 III. Sympathetic ganglionic blockade on anesthetized cats by superior cervical ganglion-nictitating membrane preparation-electrical stimulation:

Compound of LV. dose, Degree of block (04-|- Duration,

Example mgJkg. where 4+ is complete hours blockade) IV. Effect on the pupils of unanesthetized male cats:

V. Effect when the compound of Example 4 was administered intravenously to an unaesthetized male monkey in a dosage of 0.75 milligrams per kilogram of body weight was: No immediate etfects. The animal became somewhat quieter and there was possibly some dilation of the pupils. The monkey showed no evidence of dry mouth or postural hypotension.

Various modifications which will be obvious to those skilled in the art may be made in the present invention without departing from the spirit or scope thereof, and it is to be understood that we intend to limit ourselves only by the scope of the appended claims.

We claim:

1. Bis (quaternary ammonium) substituted alkane salts; wherein the alkane portion is selected from the group consisting of alkanes having 2-6 carbon atoms; wherein one quaternary ammonium group is selected from the group consisting of trimethylammonium, dimethylethylarnmonium, diethylmethylammonium, N- methylpiperidinium, N-methylmorpholinium and N- methylpyrrolidinium; wherein the other quaternary ammonium group is N-lower-alkyldecahydrobenzopyridinium; wherein the two quaternary nitrogen atoms are separated by from 2 to 4 carbon atoms, inclusive, of the alkane poytion of the, molecule; and wherein the two anions are each non-toxic acid residues.

2. Trimethylene- 1 (1 methyidecahydroquinohnium)-3-(trimethylammonium) dihromide.

3. Trimethylene 1 (1 methyl trans decahydi'oquinoliniun1)3 trimethy] ammonium) dibromide.

4.. Trimethylene 1 (1 methy1- trans decahydroquinoliniurn) -3-( 1-methy1pyn'olidinium) dibromide.

5. Ethylene 1 (1 methyldec'ahydroquinolinum) 2- (trimethylammcnium) dibromidc.

6. Trimethylene 1 (2 methyldecahydroisoquinolinium)-3-(trimethyiamrnoniurn) dibromide.

7. Trirn ethylene 1 (2 methyldeeahyroisoquino 1inium)-3-(1-n1ethy1pyrro1ic1inium) dibromide.

References Cited in the file of this patent UNITED STATES PATENTS OTHER REFERENCES Rice: J.A C.S., vol. 75 (page 4911) (1953). Gray et' 31.: J.A.C.S., v01. 77 (1955) p. 3536. 

1. BIS - (QUATERNARY AMMONIUM) - SUBSTITUTED ALKANE SALTS; WHEREIN THE ALKANE PORTION IS SELECTED FROM THE GROUP CONSISTING OF ALKANES HAVING 2-6 CARBON ATOMS; WHREIN ONE QUATERNARY AMMONIUM GROUP IS SELECTED FORM THE GROUP CONSISTING OF TRIMETHYLAMMONIUM, DIMETHYLETHYLAMMONIUM DIETHYLMETHYLAMMONIUM, NMETHYLPIPERIDINIUM, N-METHYLMORPHOLINIUM AND NMETHYLPYRROLIDINIUM; WHEREIN THE OTHER QUATERNARY AMMONIUM GROUP IS N-LOWER-ALKYLDECAHYDROBENZOPYRIDINIUM; WHEREIN THE TWO QUATERNARY NITROGEN ATOMS ARE SEPATED BY FROM 2 TO 4 CARBON ATOMS, INCLUSIVE, OF THE ALKANE PORTIONS OF THE MOLECULE; AND WHEREIN THE TWO ANIONS ARE EACH NON-TOXIC ACID RESIDUES.
 2. TRIMETHYLENE - 1 - (1 - METHYLDECAHYDROQUINOLINIUM)-3-(TRIMETHYLAMMONIUM) DIBROMIDE. 